Multiple Sclerosis and Related Disorders (2014) 3, 402–407
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
A CNS multifocal disease: Important diagnostic considerations regarding multiple sclerosis Jan-Mendelt. Tillemaa, Deborah Renauda,b, B. Mark Keegana,n a
Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA Department of Pediatrics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
b
Received 24 January 2012; received in revised form 11 September 2013; accepted 7 October 2013
1.
Introduction
A 20-year-old woman was referred to our CNS demyelinating disease clinic for assessment of seizures, cognitive decline and multifocal CNS disease. The patient had a history of seizures and leukoencephalopathy of undetermined etiology. She recently experienced worsening of clinical symptoms with progressive cognitive impairment and imbalance. She had been advised to reduce the dose of her anti-epileptic medications for concern about drug toxicity as the etiology. After reducing the antiepileptic dosage she developed status epilepticus requiring intubation and medication-induced coma for approximately 48 h. She recovered without further clinical or electrographic seizures, and she was referred to our clinic. The family reported cognitive and behavioral changes, for approximately 1 year prior to the current presentation. She had had gradually increasing difficulty with memory, frequent word-finding problems, and a reduced attention span. They described she required frequent repetition of even simple instructions. The family also noted flattened affect, describing her as apathetic and disengaged. Further, n
Corresponding author. Tel.: +1 507 538 1039; fax: +1 507 266 4419. E-mail addresses: [email protected] (J.-M. Tillema), [email protected] (D. Renaud), [email protected] (B. Mark Keegan). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.10.009
the patient had episodes of inappropriate and uncontrolled laughter. There was no aggressive behavior, suicidal thoughts or hallucinations. The gait problems were described as occasional dragging of the right foot with a tendency to lean towards the right while walking. No clear, discrete clinical relapses of neurological impairment had been noticed. Specifically, she had not had transient loss of visual acuity, diplopia, cranial nerve deficits, hemiparesis or hemisensory loss or definite symptoms of a sensory myelopathy. The patient had her first seizure at the age of 15 years suggestive of a complex partial onset seizure with secondary generalization. Prior there had been no neurological problems and the patient always had been in excellent health. At that time, she had been seen at our institution for work up of leukoencephalopathy based on findings on the MRI, which had obtained in the work up for the seizure. An extensive laboratory work up for metabolic and inherited leukoencephalopathies was unrevealing (listed in the laboratory investigations section below). There had been no prior known seizure risk factors or past history of any seizures. At the time of initial presentation she had reported episodic brief paresthesias in the upper or lower extremities. No other neurological symptoms were present at the time, nor was there a history of prior focal neurological deficits. She had not had any stroke-like episodes, abnormal involuntary movements or syncope. On neurological examination at the time she had only mild symmetrical hyperreflexia and a tremor which was felt
A CNS multifocal disease consistent with an enhanced physiologic tremor. Brain MRI at that time had shown multiple T2 signal hyperintensity (Fig. 1A) without gadolinium contrast enhancement at the time. A CSF done at that time showed seven white blood cells per microliter, with a lymphocytic predominance, no red blood cells, normal protein and glucose, but was positive for oligoclonal bands and with an increased immunoglobulin G (IgG) index. The patient had been treated with intravenous methylprednisolone followed by a brief oral prednisone taper. The working presumptive diagnoses were acute disseminated encephalomyelitis or leukoencephalopathy of uncertain etiology. Follow-up with a local pediatric neurologist was arranged with repeat clinical examination and neuroimaging. In the following years, seizures were moderately well controlled with the family recalling approximately 10–15 total seizures with breakthrough seizures often attributable to poor therapeutic compliance. She had been seizure-free for one and a half years prior to the status epilepticus on combination of oxcarbazepine and levetiracetam. She had history of migraine with aura relieved with ibuprofen and sleep. The patient had an uncomplicated pregnancy at age seventeen delivering a full term healthy daughter. She had not had recurrent infections; and no history of asthma, arthritis or heart disease. She had no skin rash or unusual birthmarks. Her immunizations were current without recent immunizations. She was a high school graduate and had been able to maintain a job until recently and was the main caregiver of her daughter, receiving assistance from her parents. According to her family, there were no prior major concerns regarding school function, work performance or social
403 interactions. There was no history of tobacco, alcohol or illicit drug use. There was no family history of multiple sclerosis or other neurological disease apart from a grandfather with Alzheimer disease.
1.1.
Neurological examination
The patient was well appearing, well nourished. General examination was unremarkable with no dysmorphic features, organomegaly, skin stigmata and no evidence of any systemic illness. The patient could not provide her own history because of severe cognitive impairment and this was therefore gained from her mother who accompanied her. The patient displayed frequent inappropriate laughter when reviewing the history. She had both motor and verbal perseveration and displayed utilization behavior, reaching for and manipulating examination tools. Formal mental status evaluation demonstrated severe impairment (18/38 on Kokmen short test of mental status). Specifically, she was oriented to person and date, but not to place. Attention was extremely poor, as was delayed recall. A score of less than 31 of 38 for patients younger than 50 years diagnoses dementia with a specificity of 93.5% and sensitivity of 86.4% (Kokmen et al., 1991). Cranial nerve examination was normal apart from a mild right sided afferent pupillary defect. Extraocular movements were full in all directions with normal smooth pursuit and saccadic eye movements without nystagmus or internuclear ophthalmoplegia. Motor examination revealed normal muscle bulk and power both proximally and distally.
Fig. 1 (A) upper line represents images obtained at age 15 years. (B) Lower images from follow up MRI at age 20 years. First three images are axial T2 FLAIR, image to the right is sagittal T2 FLAIR.
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Muscle stretch reflexes were symmetrically brisk with mildly spastic tone in both upper and lower extremities and extensor plantar responses bilaterally. There were no clear definite sensory deficits. Cerebellar examination revealed a mild postural and action tremor with mild dysmetria in both upper and lower extremities. Her gait was moderately wide based, with impaired tandem walking.
1.2.
Serum amino acids, hexosaminidase A (Tay-Sachs), glucocerebrosidases (Krabbe), arylsulfatase A (metachromatic leukodystrophy), beta-galactosidase (GM1 gangliosidosis), very long chain fatty acids (adrenoleukodystrophy) and sterol profile
Neuroimaging
Brain MRI was reviewed from initial presentation at age 15, follow up imaging at age 17, 18 and at our evaluation at her present age of 20 years. Brain MRIs done at ages 15 and 20 years old show multifocal T2 hyperintensity on FLAIR imaging without gadolinium enhancement (Fig. 1). Continued progression in the T2 lesion burden over time however results in an increasingly confluent pattern of T2 signal change with progressive cerebral atrophy. Importantly, however, the brain MRI at age 18 years old clearly showed multiple new round and ovoid gadolinium contrast-enhancing lesions, most consistent with new actively demyelinating lesions of MS (Fig. 2). Cervical and thoracic spinal cord MRI at age 20 showed multi-focal non-gadolinium enhancing T2 hyperintensity, located in the posterior segment of the cervical spinal cord (Fig. 3) again most consistent with MS. MRI of the cervical and thoracic spine had been reported normal at age 15. Focal, ovoid, non-enhancing T1 hypointensities on brain MRI consistent with MS were also found (Fig. 4).
1.3.
Laboratory investigations
CSF evaluation at age 15 years showed seven white blood cells (WBC) per microliter, protein was 20 mg/dL, glucose 67 mg/ dL. Unique oligoclonal bands were present, and IgG index was mildly elevated (0.87). Serum lactate and pyruvate were normal. Urine organic acids, mucopolysaccharides, oligosaccharides, ceramide trihexoside/sulfatide (Fabry) were normal.
Fig. 3 Spinal cord MRI (STIR) at age 20 years showing multifocal spinal cord and pontine involvement at age 20.
Fig. 2 Contrast enhancing images at age 17 years. This MRI showed 5 contrast enhancing lesions, of which 2 are shown here on the axial post gadolinium T1 images.
A CNS multifocal disease
405 (Koch et al., 2008). Although seizures have been reported to be present at onset, it tends to occur later in the course and generally they are easily treatable, and rarely are the presenting manifestation of MS (Koch et al., 2008). Lastly, severe cognitive impairment as the hallmark impairment without severe other neurological impairment is also relatively uncommon, but documented presentation of MS (Staff et al., 2009).
2.2. What diagnoses were considered more likely at onset?
Fig. 4 T1 pre-contrast image at age 15. This images show typical T1 hypointense periventricular lesion.
(cerebrotendinous xanthomatosis) were all negative. A skin biopsy was negative, showing no changes concerning for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 20 years the CSF studies were repeated with white blood cell count, protein and glucose all normal (one WBC per microliter, protein 36 mg/dL, glucose 50 mg/d,). There were 12 oligoclonal bands, unique to the CSF and IgG index was normal. Serum neuromyelitis optica immunoglobulin G (NMO-IgG) ELISA was negative. Further labs (copper levels, vitamin B12, erythrocyte sedimentation rate, anti-nuclear antibodies, rheumatic factor, anti-cyclic citrullinated peptide, thyroperoxidase antibodies) were all negative. Visual evoked potentials showed prolonged latency in the right eye.
2. 2.1.
Take home points Why was this case an atypical presentation?
There are a number of features that made this a highly challenging case. First, this patient initially presented in the pediatric age group. There have been tremendous strides recently in describing and analyzing similarities and differences between MS onset at this age compared to adult MS (Banwell et al., 2007; Chitnis et al., 2011). Diagnostic criteria have been proposed for pediatric onset demyelinating diseases (Krupp et al., 2013). It is important to make sure that typical CNS demyelinating diseases, including the most common of these, relapsing remitting MS, is considered regardless of age at onset. In our case, the lack of clear clinical relapses would be unusual for pediatric MS and more likely prompt the work up of other etiologies, which had been performed at initial presentation. The progression on the MRI over time together with the laboratory findings more likely suggest CNS demyelinating disease and the lack of clearly defined clinical relapses should not exclude this diagnosis per se. Secondly, seizures early in disease course are uncommon in MS and more frequently seen in other possible etiologies. This was the first symptom of impairment in our presented case. There is a clear increased risk of seizures in MS, occurring in approximately 2% of patients
Initially considered diagnoses included sporadic, inherited or metabolic forms of leukoencephalopathy. The atypical features with pediatric age of onset, seizures early in course, more confluent cerebral white matter disease, and the difficulty in identifying discrete clinical attacks requires strong consideration of such leukoencephalopathies. There had been extensive serological evaluations performed, as outlined in laboratory investigations, to evaluate for inherited metabolic causes and the skin biopsy assessed the possibility of CADASIL. Further genetic assessment for the notch3 gene mutation could have been assessed if CADASIL remained a strong possibility. Some sporadic and inherited leukoencephalopathies and leukodystrophies remain elusive to serological diagnoses however and some others require brain biopsies (e.g. leukodystrophy with axonal spheroids, (Keegan et al., 2008)), which was not performed in this case. The presence of focal lesions in the posterior fossa and spinal cord, the presence of earlier gadolinium enhancing ovoid cerebral MRI lesions and the unique CSF oligoclonal bands make progressive leukodystrophies less likely. Acute disseminated encephalomyelitis (ADEM) had initially been the considered diagnosis in this case. This thought process likely included the presence of inflammatory markers in the CSF consistent with inflammatory demyelinating disease in a pediatric patient and the difficulty in identifying discrete further clinical attacks. The progressive MRI lesions, persistent finding of oligoclonal bands and the absence of clear encephalopathy in the initial presentation excluded ADEM as the diagnosis.
2.3. Why is MS considered as the most likely diagnosis? An important diagnostic consideration in this case was critical review of all prior brain neuroimaging done since onset of her condition. With this, a number of critical features were discovered that make MS the most likely diagnosis. Typical gadolinium enhancing lesions had been found on review of prior MRIMRI as well as progressive ovoid T2 white matter lesions. The interval development of such T2 lesions were important to identify as in later follow up MRIs these became almost entirely confluent. In addition, even at the time where T2 and FLAIR images show confluent changes, the T1 weighted imaging continues to demonstrate some ovoid areas of hypointensity consistent with T1 “black holes”. Later in the course these T1 hypointense changes become more confluent as well but remain asymmetric.
406 Another important diagnostic clue is the imaging appearance in the brainstem as well as the cervical and thoracic spinal cord. Isolated ovoid demyelinating lesions were appreciable on spinal cord imaging. These discrete, multifocal lesions further suggest MS rather than a leukodystrophy where symmetrical longitudinal signal change along the tracts and accompanying spinal atrophy would be expected. Finally, the repeated CSF abnormalities were significant. Specifically the persistent presence of unique CSF oligoclonal bands and initial elevations in the IgG index are highly consistent with an acquired CNS demyelinating disease, such as multiple sclerosis. Other acquired CNS inflammatory diseases would unlikely have a comparable course. Although (small vessel) vasculitis can present with multifocal involvement, the duration of the disease with development of the MRI findings over multiple years together with the multifocal brainstem and spinal cord lesions would argue against this. Although CNS vasculitis remained a diagnostic consideration at the time of evaluation and cerebral biopsy could have been considered, the overall weight of the clinical and investigational evidence assisted in the decision against brain biopsy. Similarly, other CNS inflammatory etiologies were found unlikely based on the combination of the clinical history, ancillary testing and imaging findings. The absence of history and examination findings of systemic disease (including lack of arthritis, renal disease, skin rash, ophthalmologic inflammatory disease other than ON as the patient experienced) and negative rheumatological screening tests would make other inflammatory and rheumatological conditions like SLE unlikely. In addition, the absence of mucosal ulcerations and the absence of brainstem predominance make Behcet's disease unlikely. Neurosarcoidosis was deemed unlikely based on the protracted clinical course without continued gadolinium enhancement on imaging and the lack of pial gadolinium enhancement. The clinical history, e.g. without findings of chronic meningitis, and CSF findings would also be unusual for this. Similarly, limbic and viral encephalitis could be associated with significant cognitive alterations, but the pattern on imaging together with the clinical course would be unusual for this. Similarly, other CNS inflammatory etiologies. While some leukodystrophies have been reported with associated CSF changes (e.g. metachromatic leukodystrophy), further testing ruled this out along with the most common leukodystrophies. There is a single report of adult forms of Alexander's disease presenting with elevated oligoclonal bands (Tschampa et al., 2011). The MRI in our case did not have the typical appearance for Alexander's disease (van der Knaap et al., 2001, 2006). The combination of the persistent CSF findings, ovoid enhancement pattern and asymmetric typical appearance of inflammatory demyelinating brainstem and spinal cord lesions all are unlikely to fit a diagnosis of such a leukoencephalopathy, although novel leukoencephalopathies continue to be described. Brain biopsy was not performed in this case, and with the MRI not showing any significant interval change since the prior MRI plus the lack of gadolinium enhancement suggesting active ongoing inflammation, brain biopsy was considered but was felt to be likely of low diagnostic yield for other inflammatory conditions, based on these unchanged imaging
J-M. Tillema et al. findings. Subsequent MRI follow revealed no significant changes (interval 6 months). The apparent lack of clear typical relapses in the initial course does not exclude the diagnosis of MS. Many MRI brain lesions are known to be clinically silent and there often may be mild clinical symptoms that are dismissed by the patient or clinician. For example, the asymmetric prolonged VEP latencies document unilateral optic neuropathy that was clinically unrecognized. We propose that the most likely unifying diagnosis for her entire symptomatology was most likely pediatric onset Multiple Sclerosis with severe cognitive impairment. The seizures (known to occur more frequently in MS than the general population) were the first manifestation of her disease and the recent breakthrough seizures were likely related to withdrawal of her medications. She had been without further clinical seizures since treatment of status epilepticus. Although the clinical symptoms have progressive appearing components to it, recurrent inflammatory neuroimaging findings of gadolinium enhancing lesions clearly document an ongoing inflammatory component of MS. Treatment options were reviewed with the patient's family. Given the extensive damage that had occurred in the past and the very stable findings on MRI it was opted at the time to use first line interferon injections rather than going to second line agents and to follow up clinically. Patient remained stable thus far.
Role of funding source No funding was used for this study.
Conflict of interest statement Dr. Keegan has consulted for Novartis, Bionest and Bristol Meyers Squibb and receivescompensation as section editor for Neurology journal and eMedicine by WebMD and is asection editor for MS and Related Disorders. Dr. Tillema has no relevant financial disclosures to declare. He has received funding fortravel from Novartis. Dr. Renaud has no relevant financial disclosures to declare.
References Banwell B, Ghezzi A, et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007;6(10):887–902. Chitnis T, Krupp L, et al. Pediatric multiple sclerosis. Neurol Clin 2011;29(2):481–505. Keegan BM, Giannini C, et al. Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS. Neurology 2008;70(13 Pt 2):1128–33. Koch M, Uyttenboogaart M, et al. Seizures in multiple sclerosis. Epilepsia 2008;49(6):948–53. Kokmen E, Smith GE, et al. The short test of mental status. Correlations with standardized psychometric testing. Arch Neurol 1991;48(7):725–8. Krupp LB, Tardieu M, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19 (10):1261–7.
A CNS multifocal disease Staff NP, Lucchinetti CF, et al. Multiple sclerosis with predominant, severe cognitive impairment. Arch Neurol 2009;66(9):1139–43. Tschampa HJ, Greschus S, et al. MS-like presentation of Alexander disease with multifocal lesions and oligoclonal bands. J Neurol 2011;258(5):935–7.
407 van der Knaap MS, Naidu S, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001;22(3):541–52. van der Knaap MS, Ramesh V, et al. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006;66(4):494–8.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CASE REPORT
A CNS multifocal disease: Important diagnostic considerations regarding multiple sclerosis Jan-Mendelt. Tillemaa, Deborah Renauda,b, B. Mark Keegana,n a
Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA Department of Pediatrics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
b
Received 24 January 2012; received in revised form 11 September 2013; accepted 7 October 2013
1.
Introduction
A 20-year-old woman was referred to our CNS demyelinating disease clinic for assessment of seizures, cognitive decline and multifocal CNS disease. The patient had a history of seizures and leukoencephalopathy of undetermined etiology. She recently experienced worsening of clinical symptoms with progressive cognitive impairment and imbalance. She had been advised to reduce the dose of her anti-epileptic medications for concern about drug toxicity as the etiology. After reducing the antiepileptic dosage she developed status epilepticus requiring intubation and medication-induced coma for approximately 48 h. She recovered without further clinical or electrographic seizures, and she was referred to our clinic. The family reported cognitive and behavioral changes, for approximately 1 year prior to the current presentation. She had had gradually increasing difficulty with memory, frequent word-finding problems, and a reduced attention span. They described she required frequent repetition of even simple instructions. The family also noted flattened affect, describing her as apathetic and disengaged. Further, n
Corresponding author. Tel.: +1 507 538 1039; fax: +1 507 266 4419. E-mail addresses: [email protected] (J.-M. Tillema), [email protected] (D. Renaud), [email protected] (B. Mark Keegan). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.10.009
the patient had episodes of inappropriate and uncontrolled laughter. There was no aggressive behavior, suicidal thoughts or hallucinations. The gait problems were described as occasional dragging of the right foot with a tendency to lean towards the right while walking. No clear, discrete clinical relapses of neurological impairment had been noticed. Specifically, she had not had transient loss of visual acuity, diplopia, cranial nerve deficits, hemiparesis or hemisensory loss or definite symptoms of a sensory myelopathy. The patient had her first seizure at the age of 15 years suggestive of a complex partial onset seizure with secondary generalization. Prior there had been no neurological problems and the patient always had been in excellent health. At that time, she had been seen at our institution for work up of leukoencephalopathy based on findings on the MRI, which had obtained in the work up for the seizure. An extensive laboratory work up for metabolic and inherited leukoencephalopathies was unrevealing (listed in the laboratory investigations section below). There had been no prior known seizure risk factors or past history of any seizures. At the time of initial presentation she had reported episodic brief paresthesias in the upper or lower extremities. No other neurological symptoms were present at the time, nor was there a history of prior focal neurological deficits. She had not had any stroke-like episodes, abnormal involuntary movements or syncope. On neurological examination at the time she had only mild symmetrical hyperreflexia and a tremor which was felt
A CNS multifocal disease consistent with an enhanced physiologic tremor. Brain MRI at that time had shown multiple T2 signal hyperintensity (Fig. 1A) without gadolinium contrast enhancement at the time. A CSF done at that time showed seven white blood cells per microliter, with a lymphocytic predominance, no red blood cells, normal protein and glucose, but was positive for oligoclonal bands and with an increased immunoglobulin G (IgG) index. The patient had been treated with intravenous methylprednisolone followed by a brief oral prednisone taper. The working presumptive diagnoses were acute disseminated encephalomyelitis or leukoencephalopathy of uncertain etiology. Follow-up with a local pediatric neurologist was arranged with repeat clinical examination and neuroimaging. In the following years, seizures were moderately well controlled with the family recalling approximately 10–15 total seizures with breakthrough seizures often attributable to poor therapeutic compliance. She had been seizure-free for one and a half years prior to the status epilepticus on combination of oxcarbazepine and levetiracetam. She had history of migraine with aura relieved with ibuprofen and sleep. The patient had an uncomplicated pregnancy at age seventeen delivering a full term healthy daughter. She had not had recurrent infections; and no history of asthma, arthritis or heart disease. She had no skin rash or unusual birthmarks. Her immunizations were current without recent immunizations. She was a high school graduate and had been able to maintain a job until recently and was the main caregiver of her daughter, receiving assistance from her parents. According to her family, there were no prior major concerns regarding school function, work performance or social
403 interactions. There was no history of tobacco, alcohol or illicit drug use. There was no family history of multiple sclerosis or other neurological disease apart from a grandfather with Alzheimer disease.
1.1.
Neurological examination
The patient was well appearing, well nourished. General examination was unremarkable with no dysmorphic features, organomegaly, skin stigmata and no evidence of any systemic illness. The patient could not provide her own history because of severe cognitive impairment and this was therefore gained from her mother who accompanied her. The patient displayed frequent inappropriate laughter when reviewing the history. She had both motor and verbal perseveration and displayed utilization behavior, reaching for and manipulating examination tools. Formal mental status evaluation demonstrated severe impairment (18/38 on Kokmen short test of mental status). Specifically, she was oriented to person and date, but not to place. Attention was extremely poor, as was delayed recall. A score of less than 31 of 38 for patients younger than 50 years diagnoses dementia with a specificity of 93.5% and sensitivity of 86.4% (Kokmen et al., 1991). Cranial nerve examination was normal apart from a mild right sided afferent pupillary defect. Extraocular movements were full in all directions with normal smooth pursuit and saccadic eye movements without nystagmus or internuclear ophthalmoplegia. Motor examination revealed normal muscle bulk and power both proximally and distally.
Fig. 1 (A) upper line represents images obtained at age 15 years. (B) Lower images from follow up MRI at age 20 years. First three images are axial T2 FLAIR, image to the right is sagittal T2 FLAIR.
404
J-M. Tillema et al.
Muscle stretch reflexes were symmetrically brisk with mildly spastic tone in both upper and lower extremities and extensor plantar responses bilaterally. There were no clear definite sensory deficits. Cerebellar examination revealed a mild postural and action tremor with mild dysmetria in both upper and lower extremities. Her gait was moderately wide based, with impaired tandem walking.
1.2.
Serum amino acids, hexosaminidase A (Tay-Sachs), glucocerebrosidases (Krabbe), arylsulfatase A (metachromatic leukodystrophy), beta-galactosidase (GM1 gangliosidosis), very long chain fatty acids (adrenoleukodystrophy) and sterol profile
Neuroimaging
Brain MRI was reviewed from initial presentation at age 15, follow up imaging at age 17, 18 and at our evaluation at her present age of 20 years. Brain MRIs done at ages 15 and 20 years old show multifocal T2 hyperintensity on FLAIR imaging without gadolinium enhancement (Fig. 1). Continued progression in the T2 lesion burden over time however results in an increasingly confluent pattern of T2 signal change with progressive cerebral atrophy. Importantly, however, the brain MRI at age 18 years old clearly showed multiple new round and ovoid gadolinium contrast-enhancing lesions, most consistent with new actively demyelinating lesions of MS (Fig. 2). Cervical and thoracic spinal cord MRI at age 20 showed multi-focal non-gadolinium enhancing T2 hyperintensity, located in the posterior segment of the cervical spinal cord (Fig. 3) again most consistent with MS. MRI of the cervical and thoracic spine had been reported normal at age 15. Focal, ovoid, non-enhancing T1 hypointensities on brain MRI consistent with MS were also found (Fig. 4).
1.3.
Laboratory investigations
CSF evaluation at age 15 years showed seven white blood cells (WBC) per microliter, protein was 20 mg/dL, glucose 67 mg/ dL. Unique oligoclonal bands were present, and IgG index was mildly elevated (0.87). Serum lactate and pyruvate were normal. Urine organic acids, mucopolysaccharides, oligosaccharides, ceramide trihexoside/sulfatide (Fabry) were normal.
Fig. 3 Spinal cord MRI (STIR) at age 20 years showing multifocal spinal cord and pontine involvement at age 20.
Fig. 2 Contrast enhancing images at age 17 years. This MRI showed 5 contrast enhancing lesions, of which 2 are shown here on the axial post gadolinium T1 images.
A CNS multifocal disease
405 (Koch et al., 2008). Although seizures have been reported to be present at onset, it tends to occur later in the course and generally they are easily treatable, and rarely are the presenting manifestation of MS (Koch et al., 2008). Lastly, severe cognitive impairment as the hallmark impairment without severe other neurological impairment is also relatively uncommon, but documented presentation of MS (Staff et al., 2009).
2.2. What diagnoses were considered more likely at onset?
Fig. 4 T1 pre-contrast image at age 15. This images show typical T1 hypointense periventricular lesion.
(cerebrotendinous xanthomatosis) were all negative. A skin biopsy was negative, showing no changes concerning for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 20 years the CSF studies were repeated with white blood cell count, protein and glucose all normal (one WBC per microliter, protein 36 mg/dL, glucose 50 mg/d,). There were 12 oligoclonal bands, unique to the CSF and IgG index was normal. Serum neuromyelitis optica immunoglobulin G (NMO-IgG) ELISA was negative. Further labs (copper levels, vitamin B12, erythrocyte sedimentation rate, anti-nuclear antibodies, rheumatic factor, anti-cyclic citrullinated peptide, thyroperoxidase antibodies) were all negative. Visual evoked potentials showed prolonged latency in the right eye.
2. 2.1.
Take home points Why was this case an atypical presentation?
There are a number of features that made this a highly challenging case. First, this patient initially presented in the pediatric age group. There have been tremendous strides recently in describing and analyzing similarities and differences between MS onset at this age compared to adult MS (Banwell et al., 2007; Chitnis et al., 2011). Diagnostic criteria have been proposed for pediatric onset demyelinating diseases (Krupp et al., 2013). It is important to make sure that typical CNS demyelinating diseases, including the most common of these, relapsing remitting MS, is considered regardless of age at onset. In our case, the lack of clear clinical relapses would be unusual for pediatric MS and more likely prompt the work up of other etiologies, which had been performed at initial presentation. The progression on the MRI over time together with the laboratory findings more likely suggest CNS demyelinating disease and the lack of clearly defined clinical relapses should not exclude this diagnosis per se. Secondly, seizures early in disease course are uncommon in MS and more frequently seen in other possible etiologies. This was the first symptom of impairment in our presented case. There is a clear increased risk of seizures in MS, occurring in approximately 2% of patients
Initially considered diagnoses included sporadic, inherited or metabolic forms of leukoencephalopathy. The atypical features with pediatric age of onset, seizures early in course, more confluent cerebral white matter disease, and the difficulty in identifying discrete clinical attacks requires strong consideration of such leukoencephalopathies. There had been extensive serological evaluations performed, as outlined in laboratory investigations, to evaluate for inherited metabolic causes and the skin biopsy assessed the possibility of CADASIL. Further genetic assessment for the notch3 gene mutation could have been assessed if CADASIL remained a strong possibility. Some sporadic and inherited leukoencephalopathies and leukodystrophies remain elusive to serological diagnoses however and some others require brain biopsies (e.g. leukodystrophy with axonal spheroids, (Keegan et al., 2008)), which was not performed in this case. The presence of focal lesions in the posterior fossa and spinal cord, the presence of earlier gadolinium enhancing ovoid cerebral MRI lesions and the unique CSF oligoclonal bands make progressive leukodystrophies less likely. Acute disseminated encephalomyelitis (ADEM) had initially been the considered diagnosis in this case. This thought process likely included the presence of inflammatory markers in the CSF consistent with inflammatory demyelinating disease in a pediatric patient and the difficulty in identifying discrete further clinical attacks. The progressive MRI lesions, persistent finding of oligoclonal bands and the absence of clear encephalopathy in the initial presentation excluded ADEM as the diagnosis.
2.3. Why is MS considered as the most likely diagnosis? An important diagnostic consideration in this case was critical review of all prior brain neuroimaging done since onset of her condition. With this, a number of critical features were discovered that make MS the most likely diagnosis. Typical gadolinium enhancing lesions had been found on review of prior MRIMRI as well as progressive ovoid T2 white matter lesions. The interval development of such T2 lesions were important to identify as in later follow up MRIs these became almost entirely confluent. In addition, even at the time where T2 and FLAIR images show confluent changes, the T1 weighted imaging continues to demonstrate some ovoid areas of hypointensity consistent with T1 “black holes”. Later in the course these T1 hypointense changes become more confluent as well but remain asymmetric.
406 Another important diagnostic clue is the imaging appearance in the brainstem as well as the cervical and thoracic spinal cord. Isolated ovoid demyelinating lesions were appreciable on spinal cord imaging. These discrete, multifocal lesions further suggest MS rather than a leukodystrophy where symmetrical longitudinal signal change along the tracts and accompanying spinal atrophy would be expected. Finally, the repeated CSF abnormalities were significant. Specifically the persistent presence of unique CSF oligoclonal bands and initial elevations in the IgG index are highly consistent with an acquired CNS demyelinating disease, such as multiple sclerosis. Other acquired CNS inflammatory diseases would unlikely have a comparable course. Although (small vessel) vasculitis can present with multifocal involvement, the duration of the disease with development of the MRI findings over multiple years together with the multifocal brainstem and spinal cord lesions would argue against this. Although CNS vasculitis remained a diagnostic consideration at the time of evaluation and cerebral biopsy could have been considered, the overall weight of the clinical and investigational evidence assisted in the decision against brain biopsy. Similarly, other CNS inflammatory etiologies were found unlikely based on the combination of the clinical history, ancillary testing and imaging findings. The absence of history and examination findings of systemic disease (including lack of arthritis, renal disease, skin rash, ophthalmologic inflammatory disease other than ON as the patient experienced) and negative rheumatological screening tests would make other inflammatory and rheumatological conditions like SLE unlikely. In addition, the absence of mucosal ulcerations and the absence of brainstem predominance make Behcet's disease unlikely. Neurosarcoidosis was deemed unlikely based on the protracted clinical course without continued gadolinium enhancement on imaging and the lack of pial gadolinium enhancement. The clinical history, e.g. without findings of chronic meningitis, and CSF findings would also be unusual for this. Similarly, limbic and viral encephalitis could be associated with significant cognitive alterations, but the pattern on imaging together with the clinical course would be unusual for this. Similarly, other CNS inflammatory etiologies. While some leukodystrophies have been reported with associated CSF changes (e.g. metachromatic leukodystrophy), further testing ruled this out along with the most common leukodystrophies. There is a single report of adult forms of Alexander's disease presenting with elevated oligoclonal bands (Tschampa et al., 2011). The MRI in our case did not have the typical appearance for Alexander's disease (van der Knaap et al., 2001, 2006). The combination of the persistent CSF findings, ovoid enhancement pattern and asymmetric typical appearance of inflammatory demyelinating brainstem and spinal cord lesions all are unlikely to fit a diagnosis of such a leukoencephalopathy, although novel leukoencephalopathies continue to be described. Brain biopsy was not performed in this case, and with the MRI not showing any significant interval change since the prior MRI plus the lack of gadolinium enhancement suggesting active ongoing inflammation, brain biopsy was considered but was felt to be likely of low diagnostic yield for other inflammatory conditions, based on these unchanged imaging
J-M. Tillema et al. findings. Subsequent MRI follow revealed no significant changes (interval 6 months). The apparent lack of clear typical relapses in the initial course does not exclude the diagnosis of MS. Many MRI brain lesions are known to be clinically silent and there often may be mild clinical symptoms that are dismissed by the patient or clinician. For example, the asymmetric prolonged VEP latencies document unilateral optic neuropathy that was clinically unrecognized. We propose that the most likely unifying diagnosis for her entire symptomatology was most likely pediatric onset Multiple Sclerosis with severe cognitive impairment. The seizures (known to occur more frequently in MS than the general population) were the first manifestation of her disease and the recent breakthrough seizures were likely related to withdrawal of her medications. She had been without further clinical seizures since treatment of status epilepticus. Although the clinical symptoms have progressive appearing components to it, recurrent inflammatory neuroimaging findings of gadolinium enhancing lesions clearly document an ongoing inflammatory component of MS. Treatment options were reviewed with the patient's family. Given the extensive damage that had occurred in the past and the very stable findings on MRI it was opted at the time to use first line interferon injections rather than going to second line agents and to follow up clinically. Patient remained stable thus far.
Role of funding source No funding was used for this study.
Conflict of interest statement Dr. Keegan has consulted for Novartis, Bionest and Bristol Meyers Squibb and receivescompensation as section editor for Neurology journal and eMedicine by WebMD and is asection editor for MS and Related Disorders. Dr. Tillema has no relevant financial disclosures to declare. He has received funding fortravel from Novartis. Dr. Renaud has no relevant financial disclosures to declare.
References Banwell B, Ghezzi A, et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007;6(10):887–902. Chitnis T, Krupp L, et al. Pediatric multiple sclerosis. Neurol Clin 2011;29(2):481–505. Keegan BM, Giannini C, et al. Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS. Neurology 2008;70(13 Pt 2):1128–33. Koch M, Uyttenboogaart M, et al. Seizures in multiple sclerosis. Epilepsia 2008;49(6):948–53. Kokmen E, Smith GE, et al. The short test of mental status. Correlations with standardized psychometric testing. Arch Neurol 1991;48(7):725–8. Krupp LB, Tardieu M, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013;19 (10):1261–7.
A CNS multifocal disease Staff NP, Lucchinetti CF, et al. Multiple sclerosis with predominant, severe cognitive impairment. Arch Neurol 2009;66(9):1139–43. Tschampa HJ, Greschus S, et al. MS-like presentation of Alexander disease with multifocal lesions and oligoclonal bands. J Neurol 2011;258(5):935–7.
407 van der Knaap MS, Naidu S, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001;22(3):541–52. van der Knaap MS, Ramesh V, et al. Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 2006;66(4):494–8.
